GENE GUIDE

IQSEC2-Related Syndrome

This guide is not meant to take the place of medical advice. Please consult with your doctor about your genetic results and health care choices. This Gene Guide was last updated on 2024. As new information comes to light with new research we will update this page. You may find it helpful to share this guide with friends and family members or doctors and teachers of the person who has IQSEC2-Related Syndrome.
a doctor sees a patient

IQSEC2-related syndrome is also called intellectual developmental disorder, X-linked 1. For this webpage, we will be using the name IQSEC2-related syndrome to encompass the wide range of variants observed in the people identified.

IQSEC2-related syndrome happens when there are changes to the IQSEC2 gene. These changes can keep the gene from working as it should.

Key Role

The IQSEC2 gene plays a key role in brain cell growth and communication between brain cells.

Symptoms

Because the IQSEC2 gene is important for brain activity, many people who have IQSEC2-related syndrome have:

  • Intellectual disability
  • Global developmental delay
  • Autism
  • Poor or absent speech
  • Seizures
  • Lower than average muscle tone

IQSEC2-related syndrome is a genetic condition, which means that it is caused by variants in genes. Our genes contain the instructions, or code, that tell our cells how to grow, develop, and work. Genes are arranged in structures in our cells called chromosomes. Chromosomes and genes usually come in pairs, with one copy from the mother’s egg, and one copy from the father’s sperm. 

We each have 23 pairs of chromosomes. One pair, called the X and Y chromosomes, differs between biological males and biological females. Biological females have two copies of the X chromosome and all its genes, one inherited from their mother and one inherited from their father. Biological males have one copy of the X chromosome and all its genes, inherited from their mother, and one copy of the Y chromosome and its genes, inherited from their father. 

In most cases, parents pass on exact copies of the gene to their child. But the process of making the sperm and egg is not perfect. A variant in the genetic code can lead to physical issues, developmental issues, or both. 

The IQSEC2 gene is located on the X chromosome, therefore variants in this gene can affect biological males and biological females in different ways. Biological males who have variants in this gene will likely have IQSEC2-related syndrome. 

Biological females who have variants in this gene may or may not have symptoms of IQSEC2-related syndrome. Biological females who have one working copy of the gene and one non-working copy are considered to be ‘carriers’. Even if a biological female does not have signs or symptoms of the syndrome, they can pass it along to their children.

X-linked dominant conditions

IQSEC2-related syndrome usually results from a spontaneous variant in the IQSEC2 gene in the sperm or egg during development. When a brand new genetic variant happens in the genetic code it is called a ‘de novo’ genetic variant. The child can be the first in the family to have the gene variant. 

De novo variants can take place in any gene. We all have some de novo variants, most of which don’t affect our health. But because IQSEC2 plays a key role in development, de novo variants in this gene can have a meaningful effect. Many parents who have had their genes tested do not have the IQSEC2 gene variant found in their child who has the syndrome.

In some cases, IQSEC2-related syndrome is inherited. Biological females who inherit the IQSEC2 gene variant tend to have milder symptoms than those who have a de novo variant.

X-Linked Dominant Genetic Syndrome

Sex chromosomes
Non-carrier father
Non-carrier mother
Sex chromosomes
Genetic variant happens in X-chromosome in sperm or egg, or after fertilization
Non-carrier female
Female child with X-linked genetic condition
Male child with X-linked
genetic condition
Non-carrier
male

Why does my child or I have a change in the IQSEC2 gene?

No parent causes their child’s IQSEC2-related syndrome. We know this because no parent has any control over the gene changes that they do or do not pass on to their children. Please keep in mind that nothing a parent does before or during the pregnancy causes this to happen. The gene change takes place on its own and cannot be predicted or stopped.

Each family is different. A geneticist or genetic counselor can give you advice on the chance that this will happen again in your family. 

The risk of having another child who has IQSEC2-related syndrome depends on the genes of both biological parents. 

  • For a biological female parent who does not have the same genetic variant found in their child, the chance of having another child who has the syndrome is on average 1 percent. This 1 percent chance is higher than the chance of the general population. The increased risk is due to the very unlikely chance that more of the mother’s egg cells or the father’s sperm cells carry the same genetic variant. 
  • For a biological female parent who has the same IQSEC2 variant and is pregnant with a daughter, there is a 50 percent chance of passing on the same genetic variant and a 50 percent chance of passing on the working copy of the gene without the same IQSEC2 genetic variant. 
  • If they are pregnant with a son, there is a 50 percent chance of passing on the same genetic variant and the syndrome.  

For a symptom-free brother or sister of someone who has IQSEC2-related syndrome, the sibling’s risk of having a child who has IQSEC2-related syndrome depends on the sibling’s genes and their parents’ genes. 

  • If neither parent has the same genetic variant causing IQSEC2-related syndrome, the symptom-free sibling has a nearly 0 percent chance of having a child who would inherit IQSEC2-related syndrome.
  • If the biological mother has the same genetic variant causing IQSEC2-related syndrome, the symptom-free daughter has a 50 percent chance of also having the same genetic variant. If the symptom-free daughter has the same genetic variant as their sibling who has the syndrome, the symptom-free sibling’s chance of having a son who has IQSEC2-related syndrome is 50 percent. 

For a person who has IQSEC2-related syndrome, the risk of having a child who has the syndrome is about 50 percent.

As of 2024, at least 204 people with IQSEC2-related syndrome have been identified in a medical clinic. The first case of IQSEC2-related syndrome was described in 2008.

People who have IQSEC2-related syndrome may look different. Appearance can vary and can include some but not all of these features:

  • Smaller than average head size
  • Changes in head shape
  • Lower than average muscle tone

Scientists and doctors have only just begun to study IQSEC2-related syndrome. At this point, there are no medicines designed to treat the syndrome. A genetic diagnosis can help people decide on the best way to track the condition and manage therapies. Doctors can refer people to specialists for:

  • Physical exams and brain studies
  • Genetics consults
  • Development and behavior studies
  • Other issues, as needed

A developmental pediatrician, neurologist, or psychologist can follow progress over time and can help:

  • Suggest the right therapies. This can include physical, occupational, speech, or behavioral therapy.
  • Guide individualized education plans (IEPs).

Specialists advise that therapies for IQSEC2-related syndrome should begin as early as possible, ideally before a child begins school.

If seizures happen, consult a neurologist. There are many types of seizures, and not all types are easy to spot. To learn more, you can refer to resources such as the Epilepsy Foundation’s website: www.epilepsy.com/learn/types-seizures.

This section includes a summary of information from major published articles describing more than 130 people who have IQSEC2-related syndrome. It highlights how many people have different symptoms. To learn more about the articles, see the Sources and references section of this guide.

Symptoms of IQSEC2-related syndrome depend on sex and if the gene is inherited or new (de novo) within that person. In general, people with inherited variants tend to have less medical issues and people with de novo variants tend to have more medical issues. Females carrying inherited variants tend to be non-symptomatic or mildly affected.

Males with inherited IQSEC2 variants

  • 20 out of 56 people had seizures (36 percent)
  • 17 out of 56 people had language delays or impairment (30 percent)
  • 17 out of 56 people had autism (30 percent)
36%
20 out of 56 people had seizures.
30%
17 out of 56 people had language delays or impairment.
30%
17 out of 56 people had autism.

Males with de novo or new IQSEC2 variants

Most males with de novo variants have intellectual disability, ranging from mild to severe.

  • 44 out of 47 people had seizures (94 percent)
  • 42 out of 47 people had language delays or impairment (89 percent)
  • 14 out of 47 people had autism (30 percent)
94%
44 out of 47 people had seizures.
89%
42 out of 47 people had language delays or impairment.
30%
14 out of 47 people had autism.

Females with inherited IQSEC2 variants

  • 6 out of 22 people had seizures (27 percent)
  • 7 out of 22 people had language delays or impairment (32 percent)
  • 12 out of 22 people had autism (55 percent)
27%
6 out of 22 people had seizures.
32%
7 out of 22 people had language delays or impairment.
55%
12 out of 22 people had autism.

Females with de novo or new IQSEC2 variants

  • 27 out of 36 people had seizures (75 percent)
  • 25 out of 36 people had language delays or impairment (69 percent)
  • 14 out of 36 people had autism (39 percent)
75%
27 out of 36 people had seizures.
69%
25 out of 36 people had language delays or impairment.
39%
14 out of 36 people had autism.

Where can I find support and resources?

IQSEC2 Mutation

This group is for parents (or anyone else) who has someone in their lives with an IQSEC2 mutation.

Simons Searchlight

Simons Searchlight is an online international research program, building an ever growing natural history database, biorepository, and resource network of over 175 rare genetic neurodevelopmental disorders. By joining their community and sharing your experiences, you contribute to a growing database used by scientists worldwide to advance the understanding of your genetic condition. Through online surveys and optional blood sample collection, they gather valuable information to improve lives and drive scientific progress. Families like yours are the key to making meaningful progress. To register for Simons Searchlight, go to the Simons Searchlight website at www.simonssearchlight.org and click “Join Us.”

Sources and References

The content in this guide comes from published studies about IQSEC2-related syndrome. Below you can find details about each study, as well as links to summaries or, in some cases, the full article.

  • Zerem A. et al. Epilepsia, 57, 1858-1869, (2016). The molecular and phenotypic spectrum of IQSEC2-related epilepsy www.onlinelibrary.wiley.com/doi/full/10.1111/epi.13560
  • Levy NS. et al. International Journal of Molecular Sciences, 20, 3038, (2019). IQSEC2-associated intellectual disability and autism
    www.mdpi.com/1422-0067/20/12/3038/htm
  • Shoubridge C. et al. Human Mutation, 40, 5-24, (2019). IQSEC2 mutation update and review of the female-specific phenotype spectrum including intellectual disability and epilepsy www.pubmed.ncbi.nlm.nih.gov/30328660
  • Liu, X., Zhang, S., Wan, L., Zhang, X., Wang, H., Zhang, H., Zhu, G., Liang, Y., Yan, H., … Yang, G. (2022). IQSEC2-related encephalopathy in male children: Novel mutations and phenotypes. Frontiers in Molecular Neuroscience, 15, 984776. https://pubmed.ncbi.nlm.nih.gov/36267700/
  • Mastrangelo, M., Greco, C., Tolve, M., Bartolini, E., Russo, A., Nicita, F., Pruna, D., Galli, J., Favaro, J., … Pisani, F. (2024). Epilepsy phenotypes across the different age-ranges in IQSEC2-related encephalopathy: An Italian multicentre retrospective cohort study. Seizure, 119, 119-127. https://pubmed.ncbi.nlm.nih.gov/38851096/

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